We propose to study three major areas of closely related research concerning the chemical pathology and the immunologic basis of demyelination in multiple sclerosis and the biochemical and genetic basis of myelinogenesis in a unique murine hypermyelination model. (1) A major goal of the first area is to furnish reliable data on the chemical composition of MS CNS tissues, especially that of spinal cord, cord myelin, and the plaques, and to define the biochemical basis of myeline breakdown and repair. There has not been any reliable diagnostic procedure for MS. We have developed several novel and highly sensitive procedures for analyzing a number of myelin-associated components. These procedures are designed for the small amounts of CSF available from individual patients and should be useful in providing objective and reliable indices for active demyelination in MS patients. (2) Immunological research in MS has been extensive but has not yet answered important questions regarding etiology, diagnosis and treatment. However, there is strong evidence that an autoimmune mechanism may play an important role in the pathogenesis of this disease. The autoantigen(s) that are involved in myelin and oligodendroglial degeneration in MS have not been clearly defined. We can gain a better understanding of the nature of the specific antigens by producing experimental disease in animals with various compounds, particularly the compounds that are specifically localized in CNS myelin and oligodendroglia. Additionally, the use of sensitive solid-phase radioimmunoassay procedures for the detection of circulating antibodies in MS should help answer the crucial question regarding the nature of the autoantigen. (3) Finally, our plan to study myelinogenesis in a unique hypermyelination model should provide us with a better understanding of the effect of thyroid hormone on myelinogenesis, the regulation of myelin synthesis, and the genetic factors governing myelination. An application of this study is, of course, to consider the possibility of applying hormonal therapy to enhance the remyelination process in MS patients. The knowledge obtained from the entire project should be essential in improving our diagnostic capability, in devising rational and effective therapies for MS, as well as in providing vital information on myelinogenesis and its normal function.